PMID- 21059928
OWN - NLM
STAT- MEDLINE
DCOM- 20110120
LR  - 20220129
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 47
DP  - 2010 Nov 23
TI  - NADPH oxidase-mediated reactive oxygen species production activates 
      hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia 
      treatment.
PG  - 20477-82
LID - 10.1073/pnas.1006646107 [doi]
AB  - Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and 
      chemotherapy because it causes tumor reoxygenation. However, the detailed 
      molecular mechanisms of how HT enhances tumor oxygenation have not been 
      elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1 
      (HIF-1) in tumors and its downstream targets, vascular endothelial growth factor 
      (VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1 
      activation and up-regulation of its downstream genes, HT also enhances tumor 
      perfusion/vascularization and decreases oxygen consumption. As a result, tumor 
      hypoxia is reduced after HT, suggesting that these physiological changes 
      contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator 
      of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a 
      role in HT-induced tumor reoxygenation by transactivating its downstream targets. 
      We demonstrate that NADPH oxidase-mediated reactive oxygen species production, as 
      a mechanism, up-regulates HIF-1 after HT. Furthermore, we determine that this 
      pathway is initiated by increased transcription of NADPH oxidase-1 through the 
      ERK pathway. In conclusion, this study determines that, although HIF-1 is a good 
      therapeutic target, the timing of its inhibition needs to be optimized to achieve 
      the most beneficial outcome when it is combined with other treatments of HT, 
      radiation, and chemotherapy.
FAU - Moon, Eui Jung
AU  - Moon EJ
AD  - Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
FAU - Sonveaux, Pierre
AU  - Sonveaux P
FAU - Porporato, Paolo E
AU  - Porporato PE
FAU - Danhier, Pierre
AU  - Danhier P
FAU - Gallez, Bernard
AU  - Gallez B
FAU - Batinic-Haberle, Ines
AU  - Batinic-Haberle I
FAU - Nien, Yu-Chih
AU  - Nien YC
FAU - Schroeder, Thies
AU  - Schroeder T
FAU - Dewhirst, Mark W
AU  - Dewhirst MW
LA  - eng
GR  - P01 CA042745/CA/NCI NIH HHS/United States
GR  - P01CA42745-20/CA/NCI NIH HHS/United States
GR  - 243188/ERC_/European Research Council/International
GR  - P01CA42745-22/CA/NCI NIH HHS/United States
GR  - P01CA42745-21/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20101108
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA Primers)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (PDK1 protein, human)
RN  - 0 (Pdk1 protein, mouse)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Blotting, Western
MH  - Cell Hypoxia/physiology
MH  - Cell Line, Tumor
MH  - DNA Primers/genetics
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - Gene Expression Regulation/*physiology
MH  - Humans
MH  - *Hyperthermia, Induced
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Immunohistochemistry
MH  - Lactic Acid/blood
MH  - Mice
MH  - NADPH Oxidases/*metabolism
MH  - Neoplasms/*metabolism/*therapy
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
MH  - Reactive Oxygen Species/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Vascular Endothelial Growth Factor A/metabolism
PMC - PMC2996638
COIS- The authors declare no conflict of interest.
EDAT- 2010/11/10 06:00
MHDA- 2011/01/21 06:00
PMCR- 2011/05/23
CRDT- 2010/11/10 06:00
PHST- 2010/11/10 06:00 [entrez]
PHST- 2010/11/10 06:00 [pubmed]
PHST- 2011/01/21 06:00 [medline]
PHST- 2011/05/23 00:00 [pmc-release]
AID - 1006646107 [pii]
AID - 201006646 [pii]
AID - 10.1073/pnas.1006646107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20477-82. doi: 
      10.1073/pnas.1006646107. Epub 2010 Nov 8.